The present invention relates to a method for the preparation of the well-known antidepressant drug citalopram,1-[3-(dimethylamino)propyl]-1-(4fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile.
Citalopram is a well-known antidepressant drug that has now been on the market for some years and has the following structure: 
It is a selective, centrally acting serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor, accordingly having antidepressant activities. The antidepressant activity of the compound has been reported in several publications, eg. J. Hyttel Prog. Neuro-Psychopharmacol. and Biol. Psychiat. 1982, 6, 277-295 and A. Gravem Acta Psychiatr. Scand. 1987, 75, 478-486. The compound has further been disclosed to show effects in the treatment of dementia and cerebrovascular disorders, EP-A-474580.
Citalopram was first disclosed in DE 2,657,013 , corresponding to U.S. Pat No. 4,136,193. This patent publication describes the preparation of citalopram by one method and outlines a further method which may be used for preparing citalopram.
According to the process described, the corresponding 1-(4fluorophenyl)-1,3dihydro-5-isobenzofurancarbonitrile is reacted with 3-(N,N-dimethylamino)propyl-chloride in the presence of methylsulfinylmethide as condensing agent. The starting material was prepared from the corresponding 5-bromo derivative by reaction with cuprous cyanide.
International patent application No. WO 98/019511 discloses a process for the manufacture of citalopram wherein a (4- (cyano, alkyloxycarbonyl or alkylamninocarbonyl)-2-hydroxymethylphenyl-(4-fluorophenyl)methanol compound is subjected to ring closure. The resulting 5-(alkyloxycarbonyl or alkylaminocarbonyl)-1-(4fluorophenyl)-1,3-dihydroisobenzofuran is converted to the corresponding 5-cyano derivative and the 5-cyano derivative is then alkylated with a (3-dimethylamino)propylhalogenide in order to obtain citalopram.
It has now, surprisingly, been found that citalopram may be manufactured by a novel favourable process where 5-cyano-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran is alkylated with a compound which may be converted to a dimethylaminopropyl group.
The alkylation process according to the invention is particularly advantageous because the formation of by-products by polymerisation of the alkylating agent is avoided whereby a reduction in the amount of alkylating reagent used is made possible. In addition, the process of the invention provides high yields.
The present invention relates to a method for the preparation of citalopram comprising reaction of a compound of formula (I) 
with a compound having the formula 
wherein X is a suitable leaving group and R is xe2x80x94CH2xe2x80x94Oxe2x80x94Pg, xe2x80x94CH2xe2x80x94NPg1Pg2, xe2x80x94CH2xe2x80x94NMePg1, xe2x80x94COxe2x80x94N(CH3)2, xe2x80x94CH(OR1)(OR2), xe2x80x94C(OR4)(OR5)(OR6), xe2x80x94COOR3, xe2x80x94CH2xe2x80x94COxe2x80x94NH2, xe2x80x94CHxe2x95x90CHR7 or xe2x80x94COxe2x80x94NHR8 wherein Pg is a protection group for an alcohol group, Pg1 and Pg2 are protection groups for an amino group, R1 and R2 are independently selected from alkyl, alkenyl, alkynyl and optionally alkyl substituted aryl or aralkyl groups or R1 and R2 together form a chain of 2 to 4 carbon atoms, R3, R4, R5, R6 and R7 are independently selected from alkyl, alkenyl, alkynyl and optionally alkyl substituted aryl or aralkyl and R8 is hydrogen or methyl; to form a compound of the formula 
wherein R is as defined above; followed by conversion of the group R to a dimethylaminomethyl group and isolation of citalopram in the form of the base or as a pharmaceutically acceptable salt thereof.
In a first embodiment of the invention, the compound of formula (I) is reacted with a compound of formula (II) wherein R is xe2x80x94CH2xe2x80x94Oxe2x80x94Pg, wherein Pg is a protection group for an alcohol group, followed by removal of the protection group to form the corresponding alcohol of the formula 
The alcohol group is then converted to a feasible leaving group such as halogen or xe2x80x94Oxe2x80x94SO2xe2x80x94R0 wherein R0 is alkyl, or optionally alkyl substituted aryl or aralkyl, and the resulting compound is then
a) reacted with dimethylamin or a metal salt thereof to form citalopram,
b) reacted with methylamin to form a compound of formula (XII) below followed by reductive amination to form citalopram, or
c) reacted with an azide followed by reduction to form the corresponding amino compound of formula (VI) below and thereafter methylation or reductive amination to form citalopram.
In a second embodiment, the compound of formula (I) is reacted with a compound of formula (II) wherein R is xe2x80x94COxe2x80x94N(CH3)2, followed by reduction of the resulting compound of the formula 
to form citalopram.
In a third embodiment, the compound of formula (I) is reacted with a compound of formula (II) wherein R is xe2x80x94CH2xe2x80x94N(Pg1)(Pg2) where Pg1 or Pg2 are protection groups for an amino group and thereafter removal of the protection groups to form a compound of formula 
followed by methylation of the free amino group or reductive amination to form citalopram.
In a fourth embodiment, citalopram may be prepared by reaction of a compound of formula (I) with a compound of formula (II) wherein R is xe2x80x94CH(OR1)(OR2) or xe2x80x94C(OR4)(OR5)(OR6) where R1, R2, R4, R5 and R6 are as defined above to form a compound of the formula (VIIa) or (VIIb)
wherein R1, R2, R4, R5 and R6 are as defined above, followed by deprotection of the compound of formula (VIIa) or (VIIb) and consecutively reductive amination of the resulting aldehyde with dimethylamin to form citalopram.
In a fifth embodiment, citalopram may be prepared by reaction of a compound of formula (I) with a compound of formula (II) wherein R is xe2x80x94COOR3 and R3 is as defined above to form a compound of the formula 
wherein R3 is as defined above, which is then converted to an amide of formula (V) or an alcohol of formula (IV) which is converted to citalopram as described above.
In a sixth embodiment, the invention relates to a method for the preparation of citalopram wherein a compound of formula (I) is reacted with a compound of formula (II) wherein R is xe2x80x94CH2xe2x80x94CONH2 to form a compound of formula 
which is treated with hypohalide to form a compound of formula 
followed by methylation of the free amino group or reductive amination to form citalopram.
In a seventh embodiment, the invention relates to a method for the preparation of citalopram by reaction of a compound of formula (I) with a compound of formula (II) wherein R is xe2x80x94CHxe2x95x90CHR7 to form a compound of formula 
wherein R7 is as defined above, which is oxidised to form a compound of formula 
followed by reductive amination with dimethylamin to form citalopram.
In a eight embodiment, the invention relates to a process for the preparation of citalopram wherein the compound of formula (I) is reacted with a compound of formula (II) wherein R is xe2x80x94CH2xe2x80x94Me(Pg1) followed by removal of the protection group to form a compound of formula 
and thereafter methylation of the amino group or reductive amination to form citalopram.
In a final embodiment, the invention relates to a method for the preparation of citalopram wherein the compound of formula (I) is reacted with a compound of formula (II) wherein R is xe2x80x94COxe2x80x94NHR8 wherein R8 is hydrogen or methyl, followed by reduction of the resulting compound of the formula 
wherein R8 is as defined above, to form a compound of formula 
wherein R8 is as defined above, followed by methylation or reductive amination to form citalopram.
In another aspect, the present invention provides the novel intermediates of the general formula (III), (IV), (VI), (XI) and (XII).
In yet another aspect, the present invention relates to an antidepressant pharmaceutical composition comprising citalopram manufactured by the process of the invention.
The alkylation step where the compound of formula (I) is reacted with a compound of formula (II) is suitably carried out by treatment of the compound of formula (I) with a base such as for example LDA ( lithiumdiisopropylamine), LiHMDS (hexamethyldisilasan lithium), NaH, NaHMDS (hexamethyldisilasan sodium) and metalalkoxides such as NaOMe, KOMe, LiOMe, NaOtertBu, KOtertBu and LiOtertBu in an aprotic organic solvent such as THF (tetrahydrofurane), DMF (dimethylformamide), NMP (N-methylpyrrolidon), ethers such as diethylether or dioxalane, toluene, benzene, or alkanes and mixtures thereof. The anion formed is then reacted with a compound of formula (II) whereby a group of formula xe2x80x94CH2xe2x80x94CH2xe2x80x94R is introduced into position 1 of the isobenzofuranyl ring system.
Leaving groups X, may be a halogenide or a sulphonate of formula xe2x80x94Oxe2x80x94SO2xe2x80x94R0 wherein R0 is alkyl, or optionally alkyl substituted aryl or aralkyl. Suitably, R0 is methyl or p-methylphenyl.
The substituents R1 and R2 are preferably alkyl, or aralkyl or R1 and R2 together form a chain of 2 to 4 carbon atoms. Suitably, R1 and R2 are identical.
The substituents R3, R4, R5 and R6 are preferably alkyl, or aralkyl. Suitably, R4, R5 and R6 are identical.
R7 is preferably alkyl or aralkyl.
The alcohol protecting group Pg may be a trialkylsilyl group, a benzyl group or a tetrahydropyranyl group (THP).
According to the invention, the alcohol protecting group is removed to form the compound of formula (IV) using conventional methods for removal of the protection group in question.
Thus, where the protecting group is trialkylsilyl the protecting group may be removed by treatment with a base, an organic or mineral acid or a flouride such as KF or trialkylaminoflouride.
Where Pg is benzyl, the protecting group may be removed by reduction using Pd/C or Pt/C as a catalyst.
Where Pg is a tetrahydropyranyl (THP) group, the protecting group may be removed by treatment with an organic or mineral acid, or resins carrying H+ groups such as Dowex H+ or Amberlyst.
The alcohol group in the compound of formula (IV) is converted to a feasible leaving group such as halogen, or a sulphonate of formula xe2x80x94Oxe2x80x94SO2xe2x80x94R0 wherein R0 is as defined above, by reaction with reagents such as thionylchloride, mesylchloride, tosylchloride, etc.
The resulting compound is then reacted with dimethylamin or a metal salt thereof, e.g. M+, xe2x88x92N(CH3)2 wherein M+ is Lixe2x88x92 or Na+. The reaction is suitably carried out in an aprotic organic solvent such as THF (tetrahydrofurane), DMF (dimethylformamide), NMP (N-methyl pyrrolidon), ethers such as diethylether, or dioxalane, toluene, benzene, or alkanes and mixtures thereof. The compound of formula (IV) carrying a suitable leaving group may also be converted to citalopram by reaction with dimethylammonium chloride in presence of a base. Alternatively, the compound of formula (IV) carrying a suitable leaving group, such as a sulphonate of formula xe2x80x94Oxe2x80x94SO2xe2x80x94R0 wherein R0 is as defined above, may be reacted with an azide, such as sodium azide, followed by reduction using Pd/C as a catalyst to form a compound of formula (VI) and thereafter methylation or reductive amination to form Citalopram.
The compound of formula (IV) carrying a suitable leaving group, may also be converted to citalopram by reaction with methylamine to form a compound of formula (XII) above, followed by methylation or reductive amination to form Citalopram.
The reduction of the amide of formula (V) is conveniently carried out in toluene using Red-Al as a reducing agent.
Suitable groups Pg1 and Pg2 are aralkyl or xe2x80x94Oxe2x80x94SO2xe2x80x94R0 groups wherein R0 is as defined above, typically benzyl or tosyl, or Pg1 and Pg2 together with the N atom to which they are attached form an optionally substituted phthalimide group.
The protecting groups, Pg1 and Pg2 may be removed using conventional methods for removal of such protective groups. The phthalimide groups may thus be converted to an amino group by treatment with hydrazin or methylamine and ethanol.
Where the protecting group is an aralkyl group, such as benzyl, it may be removed by reduction, typically in presence of Pd/C or Pt/C as a catalyst.
The sulphonate groups of formula xe2x80x94Oxe2x80x94SO2xe2x80x94R0 may be removed by treatment with Red-Al.
The free amino group in the compound of formula (VI) may be methylated with methylating agents such as MeI and Me2SO4, wherein Me is methyl. The methylation is carried out using conventional procedures for carrying out such reactions.
Alternatively, citalopram is formed by reductive amination. According to this procedure, the compound of formula (VI) is reacted with compounds such as formaldehyde, paraformaldehyde or trioxan in presence of a reducing agent such as NaBH4 or NaBH3CN. The reductive amination is carried out using conventional procedures for carrying out such reactions.
The compound of formula (VIIa) or (VIIb) may suitably be converted to the corresponding aldehyde by treatment with an organic or mineral acid or with resins carrying H+ groups such as Dowex H+ or Amberlyst.
The resulting aldehyde may be converted to citalopram by reductive amination, i.e. by reaction with dimethylamine in the presence of a reducing agent such as NaBH4 or NaBH3CN. Dimethylamine may be added to the reaction in the form of the dimethylammonium chloride salt.
The ester derivative of formula (VIII) may be converted to citalopram via the corresponding alcohol of formula (IV) by reduction of the ester using Red-Al as a reducing agent or via the corresponding amide of formula (V) by reaction of the ester with NH(Me)2 or a metal salt thereof.
Suitable, the agent useful for conversion of a compound of formula (IX) to a compound of formula (VI) is NaOH/Br2.
Oxidation of the compound of formula (X) may be carried out by treatment of the compound with ozone in a polar solvent such as alcohol, water, acetic acid or esters thereof. Alternatively, the compound of formula (X) may be treated with oxidation agents such as NaIO4, OsO4/NaIO4 and KMnO4.
The reductive amination of a compound of formula (XI) may suitably be carried out by reaction with dimethylamin in presence of a reducing agent such as NaBH4 or NaBH3CN. Dimethylamine may be added to the reaction in the form of dimethylammonium chloride.
The amino group in the compounds of formula (XII) and (XIV) may be methylated with methylating agents such as MeI and Me2SO4, wherein Me is methyl. The methylation is carried out using conventional procedures for carrying out such reactions.
Alternatively, the amino group in the compounds of formula (XII) and (XIV) may be methylated by reductive amination. According to this procedure, the compound of formula (XII) or (XIV) is reacted with compounds such as formaldehyde, paraformaldehyde or trioxan in presence of a reducing agent such as NaBH4 or NaBH3CN. The reductive amination is carried out using conventional procedures for carrying out such reactions.
The reaction conditions, solvents, etc. used for the reactions described above are conventional conditions for such reactions and may easily be determined by a person skilled in the art.
The starting material of formula (I) may be prepared as described in U.S. Pat. No. 4,136,193 or as described in WO 98/019511.
The compounds of formula (II) are commercially available or may be prepared from commercially available starting materials using conventional techniques.
Citalopram is on the market as an antidepressant drug in the form of the racemate. However, in the near future the active S-enantiomer of citalopram is also going to be introduced to the market.
S-citalopram may be prepared by separation of the optically active isomers by chromatography.
Throughout the specification and claims, the term alkyl refers to a branched or unbranched alkyl group having from one to six carbon atoms inclusive, such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl, 2,2-dimethyllethyl and 2- methyl-1-propyl.
Similarly, alkenyl and alkynyl, respectively, designate such groups having from two to six carbon atoms, including one double bond or triple bond respectively, such as ethenyl, propenyl, butenyl, ethynyl, propynyl and butynyl.
The term aryl refers to a mono or bicyclic carbocyclic aromatic group, such as phenyl and naphthyl, in particular phenyl.
The term aralkyl refers to aryl-alkyl, wherein aryl and alkyl is as defined above.
Optionally alkyl substituted aryl and aralkyl refers to aryl and aralkyl groups which may optionally be substituted with one or more alkyl groups.
Halogen means chloro, bromo or iodo.
Citalopram may be used as the free base, in particular the free base in crystalline form, or as a pharmaceutically acceptable acid addition salt thereof. As acid addition salts, such salts formed with organic or inorganic acids may be used. Exemplary of such organic salts are those with maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bismethylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, paminobenzoic, glutamic, benzene sulfonic and theophylline acetic acids, as well as the 8halotheophyllines, for example 8bromotheophylline. Exemplary of such inorganic salts are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids.
The acid addition salts of the compounds may be prepared by methods known in the art. The base is reacted with either the calculated amount of acid in a water miscible solvent, such as acetone or ethanol, with subsequent isolation of the salt by concentration and cooling, or with an excess of the acid in a water immiscible solvent, such as ethylether, ethylacetate or dichloromethane, with the salt separating spontaneously.
The pharmaceutical compositions of the invention may be administered in any suitable way and in any suitable form, for example orally in the form of tablets, capsules, powders or syrups, or parenterally in the form of usual sterile solutions for injection.
The pharmaceutical formulations of the invention may be prepared by conventional methods in the art. For example, tablets may be prepared by mixing the active ingredient with ordinary adjuvants and/or diluents and subsequently compressing the mixture in a conventional tabletting maschine. Examples of adjuvants or diluents comprise: Corn starch, potato starch, talcum, magnesium stearate, gelatine, lactose, gums, and the like. Any other adjuvant or additive, colourings, aroma, preservatives etc. may be used provided that they are compatible with the active ingredients.
Solutions for injections may be prepared by solving the active ingredient and possible additives in a part of the solvent for injection, preferably sterile water, adjusting the solution to the desired volume, sterilising the solution and filling it in suitable ampoules or vials. Any suitable additive conventionally used in the art may be added, such as tonicity agents, preservatives, antioxidants, etc.